ORIGINAL ARTICLE

The Interpretation of the EEG in Stupor and Coma

Richard P. Brenner, MD

Abstract: This review discusses a variety of causes of stupor and coma and associated electroencephalographic (EEG) ndings. These include metabolic disturbances such as hepatic or renal dysfunction, which are often characterized by slowing of background rhythms and triphasic waves. Hypoxia and drug intoxications can produce a number of abnormal EEG patterns such as burst suppression, alpha coma, and spindle coma. Structural lesions, either supra- or infratentorial, are reviewed. EEGs in the former may show focal disturbances such as delta and theta activity, epileptiform abnormalities, and attenuation of faster frequencies. In infratentorial lesions, the EEG may appear normal, particularly with a pontine lesion. Some patients may be encephalopathic because of ongoing epileptic activity with minimal or no motor movements. This entity, nonconvulsive status epilepticus (NCSE), is difcult to diagnose in obtunded/comatose patients, and an EEG is required to verify the diagnosis and to monitor treatment. Several EEG patterns and their interpretation in suspected cases of NCSE such as periodic lateralized epileptiform discharges (PLEDs), bilateral independent periodic lateralized epileptiform discharges (BIPLEDs), generalized periodic epileptiform discharges (GPEDs), and triphasic waves are reviewed. Other entities discussed include the locked-in syndrome, neocortical death, persistent vegetative state, brainstem death, and brain death. Key Words: coma, EEG, encephalopathy, nonconvulsive status epilepticus (The Neurologist 2005;11: 271284)

espite advances in neuroimaging, the electroencephalogram (EEG) remains a valuable tool in the evaluation of stuporous and comatose patients. These recordings are usually performed in the intensive care unit and are often contaminated by artifacts arising from monitoring equipment, life support systems, and personnel. The use of additional electrodes, monitoring the electrocardiogram, body movements (eg, body, tongue, and eye) and respiration, and temporary disconnection of other equipment may be needed to identify the noncerebral origin of such activity (Fig. 1). When recording comatose patients, it is important to test for reactivity, which is dened as a change in EEG
From the University of Pittsburgh, Pittsburgh, Pennsylvania. Reprints: Richard P. Brenner, MD, WPIC, Room 111, 3811 OHara Street, Pittsburgh, PA 15213. E-mail: brennerrp@upmc.edu. Copyright 2005 by Lippincott Williams & Wilkins ISSN: 1074-7931/05/1105-0271 DOI: 10.1097/01.nrl.0000178756.44055.f6

activity after stimulation. The recording should be continued for sufcient time without stimulation so that the ongoing EEG activity can be studied and the presence or absence of spontaneous variability determined. Painful or auditory stimuli should be applied when both the patient and surroundings are relatively quiet. If reactivity is present, the EEG may show an attenuation of ongoing activity or an increase in amplitude, which is usually accompanied by the appearance of slower-frequency activity (Fig. 2). Reactivity indicates a lighter level of coma, and because the prognosis in most cases of coma is related to severity more than etiology, this is generally a good sign. However, with patients in coma secondary to a drug intoxication in which recovery will usually occur if appropriate treatment is instituted, the presence or absence of reactivity on the EEG is of less value regarding prognosis. The EEG may indicate that the alteration of consciousness is the result of: 1) diffuse physiological brain dysfunction, particularly hepatic, renal, or some drug intoxications; 2) a focal brain lesion, supratentorial mass lesions compressing the diencephalic and mesencephalic reticular formation, diffuse bihemispheric structural lesions, or infratentorial mass or destructive lesions; or 3) continued epileptic activity without convulsive movements. One of the limitations of the EEG is its lack of specicity. For example, focal continuous polymorphic delta activity (PDA) is usually indicative of a focal structural cerebral lesion. However, the variety of pathologic disturbances capable of producing this EEG abnormality is diverse and includes an infarct, tumor, hemorrhage, and other focal lesions. Diffuse slowing of background rhythms is seen in various encephalopathies regardless of etiology. The EEG may be of prognostic value if the etiology of the coma is known. If not, then serial EEGs are needed to indicate the progression of the encephalopathy. This review emphasizes the role of conventional visual EEG analysis in the evaluation of adults with alteration of consciousness. Several recent studies have reviewed continuous digital-video EEG monitoring in the intensive care unit, including the use of quantied EEG analysis.15 It is expected that this area will grow considerably in the future.

METABOLIC ENCEPHALOPATHY
A leading cause of coma is diffuse or metabolic brain dysfunction. With progression from lethargy to coma, there is diffuse slowing of background rhythms from alpha to theta and, subsequently, delta activity.6 The degree of slowing usually parallels the degree of alteration of consciousness and

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ogy. Foley et al7 described blunt spike-and-slow wave complexes in patients with liver disease. These waveforms were subsequently termed triphasic waves by Bickford and Butt8 and consist of bursts of moderate to high amplitude (100 300 uV) activity, usually of 1.5 to 2.5 Hz, and often occurring in clusters (Fig. 3). Although frequently predominant in the frontal regions, occasionally they are maximal posteriorly. A fronto-occipital lag may be present. The initial negative component is the sharpest, whereas the following positive portion of the complex is the largest and is subsequently followed by another negative wave. They are bisynchronous but may show shifting asymmetries. A persistent asymmetry (not related to technical factors or a skull defect) would suggest an underlying structural lesion on the side of lower amplitude.

FIGURE 1. Respirator artifact in a 65-year-old woman. The derivation in the bottom channel consists of electrodes placed above and below the lips. The sensitivity of this channel is one tenth of the other channels.

Despite advances in neuroimaging, the electroencephalogram (EEG) remains a valuable tool in the evaluation of stuporous and comatose patients.

Triphasic waves were initially believed to be highly specic for hepatic dysfunction. Karnaze and Bickford,9 however, in a study of 50 patients whose EEGs showed triphasic waves, found etiologies to be: hepatic (28), azotemia (10), hypoxia (9), hyperosmolarity (2), and hypoglycemia (1). Bahamon-Dussan et al10 found multiple metabolic derangements to be the most common cause of triphasic waves, being present in 12 of 30 patients. Patients were either very lethargic or comatose and the mortality was 77%. Periodic sharp complexes, most often triphasic or biphasic, and occurring approximately every second, can also be seen in patients with degenerative disorders such as Creutzfeldt-Jakob disease
FIGURE 2. Reactivity in a 19-year-old woman with an intraventricular hemorrhage. There is attenuation of faster frequencies and bursts of delta activity when the patient is called.

indicates its severity, although there are exceptions. The EEG may also show intermittent bursts of rhythmic delta activity in a generalized distribution. In adults, this is usually maximal anteriorly and is referred to as frontal intermittent rhythmic delta activity (FIRDA). Although a diffusely slow record indicates cerebral dysfunction, it is not specic for a single etiology. Possibilities would include a host of metabolic toxic disturbances, inammatory processes, and head trauma. Several of these entities are discussed in further detail in the following sections.

Hepatic
Some patterns in metabolic encephalopathies, although not pathognomonic, are often suggestive of a specic etiolFIGURE 3. Triphasic waves in a 74-year-old man with renal failure. 2005 Lippincott Williams & Wilkins

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(CJD). In addition, Sundaram and Blume11 found that senile dementia of the Alzheimer type was the most common diagnosis among 37 patients with triphasic waves who did not have a metabolic encephalopathy. Clearly, the causes of this EEG pattern will depend on the patient population at the institution where the study is performed.

without dialysis encephalopathy. Bursts of diffuse slow waves, usually maximal in the frontal area, were also more frequent in patients with dialysis encephalopathy, although common in both groups. In a review of EEG and clinical features in 14 patients with dialysis encephalopathy, the most characteristic EEG feature (12 patients) was paroxysmal highvoltage delta activity, usually maximal anteriorly.15 Spike-andwave activity occurred in 5; 2 patients had triphasic waves.

The EEG may be of prognostic value if the etiology of the coma is known. If not, then serial EEGs are needed to indicate the progression of the encephalopathy.

SEPSIS
Neurologic complications often occur in patients in the intensive care unit initially admitted with nonneurologic disorders. In one study, metabolic encephalopathy was the most frequently encountered neurologic complication; most often this was the result of sepsis.16 Young et al17 found that in patients with septic encephalopathy (an encephalopathy associated with an infection outside the nervous system, positive blood cultures, and without evidence for hepatic or renal dysfunction or hypoxemia), the EEG was a more sensitive index of brain function than the clinical criteria and was useful in monitoring patients.

In a study of the diagnostic specicity of triphasic waves, those occurring in hepatic encephalopathy were more likely to be associated with severe EEG background slowing than other encephalopathies with these waveforms.12 However, none of the morphologic features of triphasic waves, which included longitudinal topography, phase lag, symmetry, and longitudinal bipolar phase reversal sites, reliably distinguished hepatic encephalopathy from other forms of metabolic encephalopathy. Sundaram and Blume11 found that the etiology of triphasic waves was more closely related to the level of consciousness at the time of recording than on any of their morphologic aspects, distributional features, or nature of EEG background activity. Awake but confused patients all had nonmetabolic encephalopathies, particularly Alzheimer disease, whereas all unarousable patients had metabolic encephalopathies.

The EEG is often normal in alcohol withdrawal or may contain excessive low-amplitude fast activity.

DRUG INTOXICATION
Generalized fast activity on an EEG of a comatose patient should arouse the suspicion of drug intoxication, particularly with drugs that are known to increase beta activity on the EEG such as barbiturates or benzodiazepines. Usually, this activity is somewhat slower (10 16 Hz) than the 20- to 25-Hz beta activity seen in patients who are awake and taking these medications, and it is superimposed on a diffusely slow background (Fig. 4). With deeper levels of coma, intermittent episodes of suppression, a burst-suppression pattern, and ultimately electrocerebral inactivity (ECI) can be seen. An unusual pattern consisting of sinusoidal theta activity interrupted every few seconds by periodic slow-wave complexes has been described in phencyclidine (angel dust, PCP) intoxication.18 Generalized, bisynchronous sharp complexes, at times periodic and often with a triphasic conguration, have been described in a variety of drug-related disorders, as well as after hypoxiaischemia19,20 and in metabolic encephalopathies.21 These include baclofen,22,23 levodopa,24 lithium,25 ifosfamide,26,27 and metrizamide.28 32 Some have felt that these patterns may represent nonconvulsive status epilepticus, whereas others view it as an encephalopathy that resolves when the offending agent is discontinued. Drug intoxication can also result in other interesting EEG patterns such as an alpha coma and spindle coma, which are described in subsequent sections. Most anesthetic agents produce similar EEG changes. Barbiturates and most of the nonbarbiturate induction agents,

Renal
Renal disease shows abnormalities similar to other metabolic encephalopathies with progressive slowing of background rhythms and superimposed bursts of slow activity. Triphasic waves are also seen, the incidence being similar to that in hepatic disease (approximately 20%). Seizures and epileptiform abnormalities are more common in uremic than hepatic encephalopathy. Occasionally, with photic stimulation, there may be a photoparoxysmal or photomyogenic response. Hughes13 reviewed the correlation between multiple EEGs (362) and chemical changes in 23 uremic patients undergoing chronic hemodialysis over long periods of time (up to 18 months). Seventy percent of patients had at least one abnormal EEG. The one single serum index that correlated best with the EEG was the blood urea nitrogen, especially if the record showed a worsening. Other syndromes described in patients with renal disease undergoing dialysis include dialysis disequilibrium syndrome and progressive dialysis encephalopathy. In patients who develop dialysis disequilibrium syndrome, there is a worsening of the clinical state and EEG after dialysis. In dialysis encephalopathy syndrome, Hughes and Schreeder14 found bilateral spike-andwave complexes in 77% of patients with dialysis encephalopathy compared with only 2% in chronic renal patients
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and lorazepam was detected. The authors concluded that the endozepine origin of the stupor episodes of the patients, especially those in whom the diagnosis was based on clinical criteria alone, should be considered unproven.41 In another poorly dened entity, several elderly patients experienced unexplained transient unresponsiveness, sometimes recurrent, with the EEG showing slight slowing of background rhythms.42,43

Another type of alpha coma has been described with brainstem lesions and is discussed in a subsequent section, as is the spindle coma pattern.
FIGURE 4. Anesthetic pattern in a 65-year-old man undergoing a carotid endarterectomy.

HYPOXIA
including propofol, a short-acting intravenous agent often used in the intensive care unit, can initially cause an increase in beta activity with a loss of the alpha rhythm. As the dosage increases, the frequency of EEG activity decreases, whereas amplitude increases. A burst-suppression pattern occurs at high doses. If titrated further, electrocerebral inactivity (ECI) may result. Another drug commonly used in the intensive care unit is midazolam, which has EEG effects similar to other benzodiazepines.33 Like propofol, it may result in an alpha or spindle coma pattern, or burst suppression. In delirium resulting from drug withdrawal such as from barbiturates, spontaneous epileptiform abnormalities may occur, and there may be a photomyogenic or photoparoxysmal response. The EEG is often normal in alcohol withdrawal or may contain excessive low-amplitude fast activity. Two studies found that photomyogenic responses were extremely rare and that photoparoxysmal responses did not occur in either untreated alcohol withdrawal34 or after treatment of alcohol-related seizures.35 Kelly and Reilly36 felt that a normal or near-normal EEG in patients with gross impairment of sensorium and other signs of delirium should raise the possibility of alcohol withdrawal. Furthermore, the presence of marked abnormalities suggests other complications as being responsible for the alteration in consciousness rather than only delirium tremens.36,37 Idiopathic recurring stupor has been described with an EEG pattern of diffuse alpha activity, maximal anteriorly38 or fast (14 16 Hz), unreactive background activity.39 Flumazenil, a benzodiazepine receptor antagonist, promptly reversed the EEG changes and clinical state in these patients. Initially, it was felt that the 20 reported cases represented recurring stupor linked to endozepine-4 accumulation.40 All presented with the same clinical picture and EEG pattern (low-amplitude, 1314 Hz unreactive background activity) during stupor and transient awakening and normalization of the EEG after umazenil administration. Development of a newer, more specic toxicologic assay, however, led to a reanalysis of the blood samples that had been obtained in 9 of the 20 patients, Like drugs, hypoxia can produce a wide variety of abnormal EEG patterns.19,44 Of these, a burst-suppression pattern is associated with an extremely poor prognosis (Fig. 5). Kuroiwa and Celesia45 reviewed 11 cases of their own and previously published reports of 105 other patients with a burst-suppression pattern who were comatose after a cardiorespiratory arrest and not under the effects of central nervous system depressants. Of the 116 patients, 111 (96%) died. In some patients with a burst-suppression pattern, spontaneous movements can occur. These are usually orofaciallingual movements such as eye opening or chewing and may be misleading regarding the patients level of consciousness.46,47 In comatose patients having repetitive myoclonic jerks after an arrest, the EEG often shows the jerks to be associated with repetitive spikes, sharp waves, or triphasic waves occur-

FIGURE 5. A burst-suppression pattern in an 84-year-old woman after a cardiorespiratory arrest. The bursts were associated with eye opening. 2005 Lippincott Williams & Wilkins

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ring at approximately 1-second intervals with periods of suppression between the intervals or a burst-suppression pattern (Fig. 6). This entity, which has gone under a variety of terms, including myoclonic status epilepticus,48 status myoclonus,49 generalized status myoclonicus,50 and generalized myoclonic status epilepticus,51 is usually associated with a fatal outcome.52,53 Some patients described as subtle generalized convulsive status epilepticus by Treiman et al54 have had similar clinical and EEG ndings. A generalized periodic pattern after a cardiorespiratory arrest carries a poor prognosis.20,55,56 Often there are no associated clinical changes other than a decreased level of consciousness. Another pattern that occurs in hypoxia, as well as in metabolic encephalopathies, consists of brief (up to several seconds) intermittent periods of generalized suppression without associated bursts.57,58 This pattern is often associated with a poor prognosis. Several EEG grading systems have been proposed to aid in prognosis.55,59,60 The ratings are similar with EEGs showing normal or near-normal frequency activity being assigned low grades, whereas those with predominantly delta activity, intermittent suppression, burst suppression, and ultimately electrocerebral silence (ECS) having higher grades that reects a poorer prognosis. Synek61 classied patterns into benign, uncertain, and malignant. Benign patterns were: near-normal; rhythmic theta, reactive; frontal rhythmic delta, reactive or nonreactive; and spindle coma. Uncertain patterns were: mixed theta and delta, nonreactive; dominant delta, reactive or nonreactive; alpha-coma, reactive; and epileptiform discharges on a base of diffuse delta. Malignant categories were: low-amplitude delta ( 50 uV), nonreactive; burst suppression; suppression ( 20 uV), alpha/ theta coma, nonreactive; and epileptiform discharges with burst suppression. Further modication of the classication system resulted in greater interrater reliability.62 Several studies have reviewed early prediction of poor out-

come in hypoxicischemic coma using clinical ndings and electrophysiological studies (EEG and somatosensory evoked potential).63 66 An alpha coma pattern (Fig. 7) has been described after hypoxia67 as well as with drug intoxications. Although the frequency of the activity is in the alpha range, it is widespread, often of greatest amplitude anteriorly, and does not show the usual reactivity to passive eye opening and eye closure. Thus, it does not represent the normal physiological alpha rhythm, but rather is an abnormal pattern. In a review of 94 posthypoxic cases, only 10 of 86 patients survived when the pattern was secondary to cardiopulmonary arrest.68 In contrast, when resulting from a respiratory arrest (8 patients), 7 survived. Unfortunately, there have been few studies comparing the outcome of patients with coma associated with alpha frequency activity in the EEG with a clinically similar group of individuals who have other EEG ndings after cerebral hypoxia from cardiac arrest. One such study69 suggested that the prognosis in patients with alpha pattern coma was no worse than in other patients who had been comatose for more than 24 hours after cardiac arrest. Austin et al70 reached a similar conclusion and felt that alpha coma is a descriptive term, lacking prognostic signicance. Young et al71 reviewed alpha coma, theta coma, and alphatheta coma patterns. They felt that these patterns represented transient clinical EEG phenomena that did not differ from each other in etiology or outcome and indicated severe disturbance in thalamocortical physiology. Using serial recordings, the authors found that these patterns usually changed to a more denitive pattern within 5 days and that EEG reactivity in subsequent tracings was relatively favorable. A study of 14 comatose patients with an alphatheta coma (ATC) after cardiac arrest and a review of 283 reported cases of posthypoxic ATC suggested the existence of incomplete and complete variants of ATC.72 Incomplete ATC (the alpha/theta EEG activity was not monotonous, partially reactive, or posteriorly dominant) was associated with a full

FIGURE 6. Myoclonic status epilepticus in a 65-year-old comatose man who experienced an anoxic event 48 hours before the recording. The EEG shows generalized polyspikes occurring approximately every second. 2005 Lippincott Williams & Wilkins

FIGURE 7. An alpha coma pattern in a 68-year-old man postcardiorespiratory arrest.

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recovery, whereas complete ATC was invariably associated with a poor outcome. Kaplan et al73 retrospectively reviewed 36 patients with alpha coma pattern and performed a metaanalysis of 335 cases of alpha coma in the world literature. They stressed the importance of etiology as well as reactivity. For example, there was a very high mortality with patients with a cardiorespiratory arrest, whereas approximately 90% with drug-induced coma and this EEG pattern survived. They also found that EEG reactivity to noxious stimuli favored survival; without it, most patients died. This was independent of etiology. Another type of alpha coma has been described with brainstem lesions and is discussed in a subsequent section, as is the spindle coma pattern. The latter may be seen with hypoxia, drug intoxications, diffuse encephalopathies, as well as subtentorial or supratentorial lesions.

STRUCTURAL LESIONS Supratentorial

The EEG is usually markedly abnormal when coma is the result of a supratentorial lesion. The abnormalities are greater with acute and rapidly expanding lesions rather than with chronic, slow-growing processes. The EEG, however, is of limited value in the precise localization of the lesion within the affected hemisphere. Several types of abnormalities may be seen (Fig. 8). Often, there is continual focal PDA over the involved side or increased focal delta and theta activity. With disturbances of deeper structures, FIRDA usually appears. Other EEG abnormalities may include focal attenuation of activity, a decrease of faster frequencies over the affected side, and focal epileptiform abnormalities. Such ndings are not specic for a single etiology. A pattern often seen with acute or subacute unilateral lesions is periodic lateralized epileptiform discharges (PLEDs) (Fig. 9). Chatrian et al74 described PLEDs as consisting of lateralized complexes usually recurring every 1 to

FIGURE 9. Periodic lateralized epileptiform discharges in a 74-year-old-woman after removal of a left subdural hematoma 4 days earlier.

FIGURE 8. There is suppression of background rhythms over the left hemisphere in this 19-year-old woman with a traumatic left middle cerebral artery infarct after a motor vehicle accident. There is also rightsided slowing.

2 seconds. The complexes often consist of sharp waves or spikes that may be followed by a slow wave. Reiher et al75 proposed a classication of PLEDs that included PLEDs Plus and PLEDs Proper. PLEDs Plus consists of a brief, lowamplitude focal rhythmic activity that occurs in association with PLEDs, whereas PLEDs Proper consisted of repetitive and stereotyped PLEDs without the rhythmic discharges. PLEDs Plus is more likely to be associated with clinical seizures and seizure discharges than is PLEDs Proper. PLEDs occur in a variety of disorders, most often infarcts or tumors. They may also be seen in patients with chronic seizure disorders or old static lesions, especially when associated with recent seizures, alcohol withdrawal, or a toxicmetabolic disorder.76 The clinical picture associated with PLEDs is usually obtundation, focal seizures, and focal neurologic signs. In a review of 586 cases of PLEDs reported in the literature, Snodgrass et al77 found the etiologies to be cerebrovascular accident (35%), mass lesion (26%), infection (6%), hypoxia (2%), and other (22%). The majority of patients with herpes simplex encephalitis (HSE) have PLEDs, particularly when serial recordings are obtained. The presence of PLEDs in the EEG in a patient with suspected viral encephalitis should raise the suspicion of HSE; however, it is not pathognomonic.78 Regardless of etiology, PLEDs are a transient phenomenon. With time, the discharges usually decrease in amplitude, the repetition rate decreases, and ultimately the discharges cease. PLEDs are lateralized; however, they are often reected synchronously to a lesser degree over homologous areas in the contralateral hemisphere. In contrast, in patients with bilateral independent periodic lateralized epileptiform discharges (BIPLEDs), the complexes are asynchronous, usually differing in morphology, amplitude, rate of repetition, and site of maximal involvement (Fig. 10) De la Paz and Brenner79 reported clinical ndings in 18 patients whose EEGs showed this pattern. The most common cause of BIPLEDs was hypoxic encephalopathy (5), central nervous
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FIGURE 10. Bilateral independent periodic lateralized epileptiform discharges in an 82-year-old man status postresection of a right subdural hematoma.

system infection (encephalitis or meningitis5), and chronic seizure disorders (4). When compared with patients with PLEDs, those with BIPLEDs were more likely to be comatose (72% vs. 24%) and had a higher mortality rate (61% vs. 29%), but focal neurologic decits and focal seizures were less common.

Subtentorial
The EEG is of less value in the evaluation and prognosis of comatose patients when the lesion is subtentorial rather than supratentorial or as a result of a diffuse metabolic process. The EEG is better in assessing hemispheric function, which determines quality of survival, rather than brainstem function, which is needed for survival. However, the EEG may still be of value. As indicated earlier, an alpha pattern coma has been described in patients with brainstem lesions. This is the result of involvement of the upper pons and caudal midbrain, usually secondary to a vascular insult. With bilateral involvement of the pontine tegmentum, the patient is comatose with an EEG showing alpha activity.80 In contrast to the posthypoxic alpha pattern coma, the alpha frequency activity seen with a brainstem lesion is more posterior and shows more variability. In addition, there may be reactivity with sensory stimulation such as passive eye opening and eye closure or painful stimuli.67 Although the EEG resembles normal wakefulness, few patients survive. Patients with this type of alpha pattern coma need to be distinguished clinically from patients with a locked-in syndrome.81 83 The latter are conscious, although paralyzed and mute, and can often communicate with eye blinks. Here the lesion affects the ventral pons but does not involve the pontine tegmentum, and consciousness is not affected. Higher involvement of the midbrain and diencephalon result in coma and produce generalized slow (delta) waves that may be continuous or intermittent. Another condition that may simulate coma is psychogenic unresponsiveness. The EEG is usually normal and the alpha rhythm, if present, shows reactivity to passive eye opening and eye closure. Neurologic ndings, particu 2005 Lippincott Williams & Wilkins

larly the presence of nystagmus with oculovestibular testing, will help identify the cause of this apparently altered state of consciousness. A normal-appearing EEG in a truly comatose patient (not psychogenic coma) is indicative of a brainstem lesion. A spindle coma pattern (Fig. 11) is thought to be the result of altered function caudal to the thalamus but rostral to the pontomesencephalic junction.84 Chatrian et al85 rst described the pattern in 11 patients with head injury and concluded that the presence of slow-wave sleep activity such as spindles indicated a good prognosis. Britt et al84 reported 36 patients with nontraumatic alteration of consciousness of diverse etiologies, whose EEG activity resembled slow-wave sleep. In those patients who were comatose,21 only 4 survived, whereas the prognosis was good in patients who were stuporous or semicomatose (14 of 15 patients survived). In a study of 370 comatose patients, among whom 5.9% (22 patients) showed a spindle coma pattern, approximately one third was the result of a head injury, whereas another third was secondary to cerebral hemorrhage or cerebral hypoxia.86 The authors concluded that EEGs with spindle patterns are of dubious value in indicating the prognosis of coma, because the outcome for patients with this EEG pattern was no better than those without it. Hulihan and Syna87 reviewed EEG sleep patterns in posthypoxic stupor and coma in 14 patients. They found that the presence of spindles did not indicate a favorable prognosis but that the absence of spindles or reactivity was associated with a poor outcome (death or persistent vegetative state). Like other EEG patterns, spindle coma is not specic for a single etiology, and the prognosis is dependent on several factors, including severity of insult, type of injury, neurologic ndings, patient age, and time of recording in relation to insult. Kaplan88 studied 15 patients with spindle coma resulting from various causes and found that the outcome was favorable. EEG reactivity to noxious stimuli best predicted outcome. In reviewing the literature, they concluded that spindle coma was an EEG pattern conferring a

FIGURE 11. The EEG shows sleep spindles in this comatose 25-year-old man status postmotor vehicle accident with a head injury and receiving propofol.

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good prognosis, particularly if associated with reactivity to external stimuli. However, this was most likely the result of its respective benign or reversible underlying etiologies.

NONCONVULSIVE STATUS EPILEPTICUS

Convulsive status epilepticus (SE) is the most serious, as well as the most easily recognized type of SE, and is characterized by a loss of consciousness, recurrent or continuous convulsions, and generalized ictal activity on EEG. It is nonconvulsive status epilepticus (NCSE) that is more heterogeneous and controversial. Within this group, the terms absence status or petit mal status are usually used for those patients with generalized EEG ndings who may be ambulatory and often appear confused with repetitive automatisms, whereas those with a partial EEG onset have been termed complex partial SE (CPSE). The term NCSE is more often applied to patients who are severely obtunded or comatose with minimal or no motor movements, often with serious medical conditions. However, some investigators have used NCSE to include all the patients described, ranging from those with barely detectable mental status changes to those in coma. I prefer to subdivide NCSE based on clinical features such as degree of impairment of consciousness.89 In a recent study of 100 consecutive cases of NCSE, mortality was associated with an acute medical cause as the underlying etiology, severe mental status impairment, and development of acute complications.90 For example, in patients with an acute medical cause of NCSE, 14 of 52 patients (27%) died, whereas only one of 31 patients with epilepsy died. If there was severe mental status impairment, the mortality was 39% compared with 7% in mildly obtunded patients. Clearly, the prognosis is very different and is related to the etiology, clinical ndings such as level of consciousness, and associated comorbidities.91 Initially, ambulatory forms of NCSE are reviewed. NCSE is dened as an epileptic state lasting more than 30 minutes with some clinically evident change in mental status or behavior from baseline and ictal activity on EEG. There are 2 major categories of NCSE: generalized and partial. Numerous terms have been used to describe generalized NCSE in patients who are often confused but ambulatory92,93; absence status is the most widely used. A variety of EEG patterns have been described in generalized NCSE. Most commonly, the EEG shows more or less continuous, or frequently recurring, generalized, bilaterally synchronous, symmetric spike and wave, which may be at a frequency of 3 Hz but is often less,90,94 97 or generalized polyspike and wave discharges (Fig. 12). The EEG is extremely useful in the identication of NCSE, particularly when the cause of this acute confusional state is not clinically apparent. The behavioral alterations in generalized NCSE have sometimes resulted in an incorrect initial diagnosis of a primary psychiatric disorder98,99 such as depression, psychosis, or hysteria. There are often clues to help identify the underlying epileptic nature of this acute disturbance. Most commonly, the episodes occur in known epileptic patients (90 95%),96 although they can occur without

FIGURE 12. The EEG of a 20-year-old man in absence status epilepticus, ambulatory but confused. He had absence seizures beginning in childhood.

a history of seizures, particularly in the elderly,96,98 In this latter group, benzodiazepine withdrawal has been implicated.100,101 The presence of associated myoclonic movements such as eyelid utter and rhythmic facial or upper extremity movements is also suggestive of absence status. However, an EEG is the only means of verifying the diagnosis. Other entities in the differential diagnosis include a postictal state,102,103 drug intoxication, metabolic encephalopathy, transient global amnesia, psychiatric disorders, and complex partial status epilepticus (CPSE). In contrast to absence status, in CPSE, the EEG abnormalities usually are focal, most often affecting the temporal area, although they can become generalized. The focal EEG abnormalities may not be appreciated, particularly if the recording begins after the onset of the status. The rhythmic focal discharge that may characterize complex partial seizures can range from the delta to beta frequency. The EEG ndings may show recurrent focal seizures or a more continuous cycling with alterations of unresponsiveness and partially responsive phases. NCSE can be difcult to classify (generalized vs. partial) at times, even with ictal EEG recordings. In particular, frontal seizures may show a generalized pattern on EEG.104 Guberman et al99 felt that transitional cases of NCSE exist with lateralizing EEG features and that some cases are probably the result of secondary generalization from a temporal or frontal focus. Tomson and colleagues105 felt that most cases of NCSE represent CPSE. However, Granner and Lee,97 in a large series of patients with NCSE (85 ictal episodes in 78 patients), found that 69% of the episodes were generalized on EEG, 18% were generalized with focal predominance, and 13% were focal. The difculty in distinguishing NCSE from CPSE may, in part, explain the differences in EEG interpretation after metrizamide myelography, which has been described as either generalized31 or partial status epilepticus.29 Porter and Penry92 believed that the clinical differences between generalized and partial NCSE could help to differentiate between these 2 disorders. The former ends abruptly without postictal abnormality, whereas the latter is associated
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with postictal confusion, depression, or general malaise. Others emphasized cyclic clinical phases in patients with CPSE, alternating between total unresponsiveness with stereotyped automatisms and partial responsiveness with reactive automatisms.106 Tomson et al107 did not feel that this clinical characteristic allowed unequivocal differentiation between absence status and the continuous form of complex partial status. NCSE is difcult to diagnose in obtunded/comatose patients.108 110 A variety of terms have been used to describe these patients: subtle generalized SE,54 electrographic SE,111 SE in comatose patients,112 generalized electrographic SE,113 nontonic clonic SE,114 subclinical SE,115 and NCSE.89,116 118 Sometimes the same term has been used when describing different disorders, whereas different terms are often applied to the same clinical entity. Because these patients are often difcult to diagnose, the diagnosis is usually delayed. They may display subtle, intermittent, focal, or multifocal rhythmic movements suggestive of seizures.119 Husain et al120 felt that certain clinical features were more likely to be present in patients with NCSE compared with other types of encephalopathy. These included either a remote history of seizures or ocular movement abnormalities. NCSE can occur in a variety of disorders, including hypoxia, metabolic disturbances,111113 and after convulsive seizures.121 There are a number of EEG patterns that have been described in NCSE and some are controversial, particularly as to whether they are ictal. These include PLEDs, BIPLEDs, periodic epileptiform discharges (PEDs), which can be either focal or generalized, and generalized triphasic waves. The majority of patients with PLEDs will have seizures during the acute stage of illness. During the recording of the EEG, PLEDs usually will be transiently replaced by a new pattern if a seizure occurs, often consisting of faster rhythmic activity (Fig. 13). For this reason, PLEDs are usually considered an interictal pattern, although not all agree.122124 In several studies of NCSE, PLEDs alone were not considered an ictal pattern.125127 Pohlmann-Eden et al128 viewed PLEDs as an electrographic signature of a dynamic pathophysiological state in which unstable neurobiologic processes create an ictalinterictal continuum. BIPLEDs are much less common than PLEDs. Like PLEDs, the complexes are often replaced by a lateralized rhythmic pattern during a seizure (Fig. 14). Generalized, periodic, bisynchronous, sharp complexes, often with a triphasic conguration, have been described in a variety of drug-related disorders, metabolic encephalopathies,21 following anoxiaischemia,19 and in convulsive status epilepticus.121 Treiman et al121 described a progressive sequence of EEG changes during generalized CSE; however, others have not found this sequence of changes.112,115,123,129 Whether the nal pattern of this proposed sequence, namely generalized periodic epileptiform discharges (GPEDs) with a at background (Fig. 15), should be considered ictal is debatable.19,56,123,129 Like in patients with PLEDs or BIPLEDs, a longer recording (1 hour instead of 25 minutes) may demonstrate discrete seizures. Furthermore, although some authors have felt that PEDs may represent NCSE, others view it as an epileptic encephalopathy in which spikes and sharp waves may not
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impair clinical function, but rather reect damage from severe brain injury.130,131 Another pattern described by some as consistent with NCSE is triphasic waves. When EEGers use the term triphasic waves, they are usually implying a pattern seen with a variety of metabolic encephalopathies, particularly hepatic or renal dysfunction. However, the term triphasic can also be used to describe the morphology of the waveform in that sharp-and-slow wave complexes usually have 3 phases; hence, they are triphasic waves. Difculties in distinguishing triphasic waves from epileptiform sharp-and-slow wave complexes were initially noted by Foley et al,7 and recommendations are provided by several investigators.132134 Kaplan89 felt that triphasic waves may straddle the borders between epilepsy and encephalopathy and that the distinction between NCSE and encephalopathy can be difcult, whereas Litt et al117 felt that monorhythmic triphasic waves could be distinguished from ictal patterns. Clearly, there are times when this distinction can be difcult; hence, the terms triphasic-like waves and nonepileptiform true triphasic waves.56 Triphasic waves may increase with stimulation; this is also true of PLEDs, BIPLEDs, and GPEDs.2 In a study of 150 critically ill patients undergoing continuous EEG monitoring (with or without video), 33 patients exhibited stimulus-induced, rhythmic, periodic, or ictal discharges, which the authors termed SIRPIDs. They concluded that further research is necessary to determine the pathophysiological, prognostic, and therapeutic signicance of SIRPIDS. NCSE consists of EEG ictal episodes that are continuous or recurrent for greater than 30 minutes without improvement in clinical state or return to preictal EEG pattern between seizures. There are no agreed-on criteria to diagnose NCSE in obtunded/comatose patients. Litt et al117 described 3 EEG patterns of electrographic SE: focal, generalized, and bihemispheric (Fig. 16AC). It is relatively easy to diagnose NCSE when there are frequent focal electrographic seizures. The problem is greater with generalized spike and wave and sharp-and-slow wave complexes. The latter should not be

FIGURE 13. Left-sided electrographic discharge in the patient shown in Figure 9.

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FIGURE 15. Periodic epileptiform discharges in a 75-yearold-woman.

FIGURE 14. (A and B) (A) A left-sided electrographic seizure and (B) a right-sided seizure in the patient shown in Figure 10.

invariant. There should be a waxing and waning of these patterns for inclusion; however, this can often be a very subjective interpretation. Furthermore, changes in the pattern, if present, usually should not be only state-related. For proposed criteria of nonconvulsive seizures (NCS), which helps dene NCSE, see Young et al.135 Medications such as benzodiazepines, their effects on the EEG, and their role in diagnosis are also debated. For example, a test dose of lorazepam may complicate matters, because most EEG patterns may resolve if the patient is given an adequate dose, including triphasic waves resulting from a metabolic encephalopathy.136 Sometimes this can be shown to be the result of a state change, because the pattern recurs after painful stimulation. Improvement in the EEG after treatment does not prove that the discharges were ictal and responsible for the patients decreased responsiveness; clearly, marked clinical improvement is the preferred response. The incidence of NCSE in obtunded/comatose patients is uncertain. Towne and colleagues118 found that 8% of

comatose patients, excluding those with clinical evidence or history of seizures, were in NCSE, whereas Claassen et al1 reported that 59 of 570 critically ill patients were in NCSE. In a prospective study of 198 cases with alteration of consciousness but without convulsions, 74 (37%) showed clinical or EEG evidence of denite or probable nontonic clonic SE.114 NCSE should be considered in patients with an apparently prolonged postictal state after convulsive seizures. Jaitly et al127 studied 180 patients, ages 17 to 96 years, who were monitored after clinical SE. Of these, 96 had ictal discharges that included both CSE and NCSE. Others116 found that after CSE was controlled, EEG monitoring demonstrated that 48% had persistent electrographic seizures and 14% manifested NCSE, which was predominantly partial rather than generalized. NCSE should also be considered with unexplained alteration of mental status or coma, with or without subtle motor activity, such as facial myoclonus or nystagmoid eye movements. An EEG is the only way to verify the diagnosis, although, as has been emphasized, interpretation can be difcult. An EEG is also helpful in monitoring patients who are being treated for SE, particularly because the neurologic examination is affected by the administration of drugs such as lorazepam, midazolam, propofol, pentobarbital, or neuromuscular-blocking agents. The diagnostic criteria for NCSE are controversial, and there are no agreed-on criteria to diagnose NCSE in obtunded/comatose patients, and there is no consensus on how it should it be treated.91 Furthermore, outcome is poor and several studies113,117 suggest that treatment may not be helpful.

ELECTROCEREBRAL INACTIVITY
The end stage of coma is electrocerebral inactivity (ECI), previously called electrocerebral silence (ECS), dened as no cerebral activity over 2 uV when recording from scalp or referential electrode pairs, 10 or more cm apart with interelectrode resistances under 10,000 ohms (or impedances under 6000 ohms) but over 100 ohms137 (Fig. 17).
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FIGURE 17. A 44-year-old man in a persistent vegetative state. There is no definite cerebral activity. Eye blink artifact is present.

FIGURE 16. (A) A focal right posterior head region electrographic seizure in this 83-year-old-man in partial nonconvulsive status epilepticus (NCSE). (B) Bihemispheric NCSE in a 72-yearold woman status postresection of a bifrontalparietal meningioma. (C) Generalized NCSE in a 64-year-old-man after anoxia. 2005 Lippincott Williams & Wilkins

EEG is an optional conrmatory test in the evaluation of brain death in adults. The American EEG Society Guidelines137 discuss in detail technical standards to be used in recording patients with suspected cerebral death. These include considerations such as recording time, number of electrodes, interelectrode impedances, appropriate sensitivity and time constant, tests of reactivity, and monitoring techniques. In cases in which ECI is present and the patient is being evaluated for brain death, both hypothermia and drug intoxication, which are potentially reversible, must be excluded.137 Regarding the former, Walker et al138 state that unless the temperature is less than 32C, it does not seem to depress the EEG appreciably, whereas arterial hypotension (at or below shock levels) is a more potent depressor of EEG activity and should be considered when interpreting the EEG. They also felt that the record usually should not be performed until clinical evidence of brain death has been present for 12 hours, although this time might be shortened if the cause of coma is well established as irreversible. In practice, 6 hours is often the minimum. Occasionally, patients with a persistent vegetative state (PVS) may have ECI, although the majority show EEG activity. PVS implies permanent and total loss of forebrain function; however, many brainstem functions such as breathing, chewing, swallowing, and cranial nerve reexes are largely preserved. Similarities and contrasts between brain death and PVS have been reviewed by Young et al.135 Other patients may clinically appear brain-dead yet the EEG demonstrates cerebral activity. Such examples include brainstem death139 142 or severe polyradiculoneuropathy.143,144 Chatrian and Turella145 have critically reviewed the concept of brain death, including denition, clinical criteria, and differences between the United Kingdom and the United States, as well as other states of altered responsiveness such as selective failure of brainstem function and vegetative states.

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ACKNOWLEDGMENTS
Much of this material appeared in Brenner RP. The EEG in encephalopathy and coma. Am J End Technol 2003; 43:164 184. Reproduced with permission of the publisher. REFERENCES
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